Cutaneous Leiomyomata Research Articles

Hereditary Leiomyomatosis and Renal Cell Cancer: Clinical, Molecular, and Screening Features in a Cohort of 185 Affected Individuals

BackgroundHereditary leiomyomatosis and renal cell cancer (HLRCC) is a tumour predisposition syndrome characterised by predisposition to cutaneous and uterine leiomyomata and renal cell carcinoma (RCC). ObjectiveTo define the clinical findings, molecular genetics, and prognosis in a cohort of 69 families with a fumarate hydratase (FH) pathogenic variant and/or clinical features of HLRCC. Design, setting, and participantsClinical and molecular findings were obtained for 185 individuals from 69 families from four UK regional genetics clinics. Outcome measurements and statistical analysisAges at confirmed diagnoses, last dates of follow-up, and molecular results were attained for probands and relatives. To study the effect of potential ascertainment bias, phenotypes of probands and their affected relatives were compared. Results and limitationsA germline FH variant (19 novel and 21 known, >50% missense variants) was identified in 68/69 probands and 90 relatives. Cutaneous leiomyomata occurred in 90/185 (48.6%) individuals (mean age 45.9 yr) and uterine leiomyomata in 33/107 (30.8%) females (mean age 35.0 yr). Of 185 individuals, 23 (12.4%) had a confirmed renal tumour, and histopathology where known (n = 18) was variable: seven clear cell RCCs, nine papillary RCCs (six of type 2), one collecting duct tumour, and one tumour with oncocytic cystic morphology. Mean age at symptomatic RCC diagnosis was 44.0 yr and median survival was 21.0 mo. Eighty-one individuals underwent 187 renal imaging surveillance scans; three stage 1 RCCs were detected. Mean survival of individuals diagnosed with stage 1/2 RCC was significantly longer than those diagnosed with stage 3/4 RCC (p = 0.0004). ConclusionsManagement of HLRCC is challenging as RCC occurs in a minority of cases but is highly aggressive. This large multicentre series has identified novel features and evidence that renal screening in HLRCC detects early-stage RCCs. Patient summaryWe show that hereditary leiomyomatosis and renal cell cancer is associated with a 21% lifetime risk of renal cell carcinoma (RCC; 95% confidence interval 8.2–37.1), and renal imaging screening detects early-stage RCC.

Adrenal Nodular Hyperplasia in Hereditary Leiomyomatosis and Renal Cell Cancer

The condition hereditary leiomyomatosis and renal cell carcinoma is characterized by cutaneous leiomyomas, uterine fibroids and aggressive papillary renal cell carcinoma. A number of our patients with hereditary leiomyomatosis and renal cell carcinoma had atypical adrenal nodules, which were further evaluated to determine whether these nodules were associated with hereditary leiomyomatosis and renal cell carcinoma. Patients with hereditary leiomyomatosis and renal cell carcinoma underwent a comprehensive clinical and genetic evaluation. We reviewed the clinical presentation, anatomical and functional imaging, endocrine evaluation, pathological examination and germline mutation testing results. Of 255 patients with hereditary leiomyomatosis and renal cell carcinoma 20 (7.8%) had primary adrenal lesions, including 4 with bilateral adrenal lesions and 4 with multiple nodules. Two patients had adrenocorticotropic hormone independent hypercortisolism. A total of 27 adrenal lesions were evaluated. The imaging characteristics of 5 of these lesions (18.5%) were not consistent with adenoma by noncontrast computerized tomography criteria. Positron emission tomography was positive in 7 of 10 cases (70%). A total of 12 nodules were surgically resected from 10 adrenal glands. Pathological examination revealed macronodular adrenal hyperplasia in all specimens. Unilateral and bilateral adrenal nodular hyperplasia was detected in a subset of patients with hereditary leiomyomatosis and renal cell carcinoma. A functional endocrine evaluation is recommended when an adrenal lesion is discovered. Imaging frequently reveals lesions that are not typical of adenomas and positron emission tomography may be positive. To date no patient has had adrenal malignancy, and active surveillance of hereditary leiomyomatosis and renal cell carcinoma adrenal nodules appears justified.

Fumarate hydratase gene mutation in two young patients with sporadic uterine fibroids

Fumarate hydratase (FH) is a key enzyme of the Krebs cycle. Germline mutations in the FH gene encoding fumarate hydratase cause autosomal dominant syndromes multiple cutaneous and uterine leiomyomata and hereditary leiomyomatosis and renal cell cancer (HLRCC). Few data have been published on the role of FH gene mutation in development of uterine fibroids outside the context of multiple cutaneous and uterine leiomyomata /HLRCC. We report two FH gene mutations, one novel and one previously described, in two young patients with sporadic uterine fibroids and decreased fumarate hydratase activity in lymphocytes. In patient 1, a novel heterozygous mutation c.892G>C was found. In patient 2 we detected heterozygous mutation c.584T>C. Both the patients had a negative family history for renal cancer and cutaneous leiomyomatosis. None of the relatives, however, underwent renal imaging at the time of writing. FH mutation carriers may be easily identified by analysis of fumarate hydratase activity in blood lymphocytes. We suggest performing fumarate hydratase activity or FH mutation screening in women with onset of uterine fibroids in their 20s and family history of uterine fibroids or other HLRCC-associated malignancies.

A case report of hereditary leiomyomatosis and renal cell cancer

A 27-year-old woman, gravida 0, presented with uterine and cutaneous leiomyomata. Genetic testing confirmed hereditary leiomyomatosis and renal cell cancer syndrome, an autosomal dominant disorder caused by germline mutations in the fumarate hydratase gene. Specific screening guidelines do not exist and are often individual and treatment center dependent.

Male infertility associated with hereditary leiomyomatosis and renal cell carcinoma

To report a novel association between a cancer predisposition syndrome (hereditary leiomyomatosis and renal cell carcinoma [HLRCC]) and male infertility. Case report. University medical center adult genetics clinic. A 31-year-old male of Chinese ancestry referred for evaluation of immotile sperm. Physical examination, family history assessment, genetic testing, and cancer screening. Genetic testing results. Physical exam: cutaneous leiomyomata on the upper back and left arm. Family history: the patient has a sister with uterine leiomyomata. Genetic testing revealed a mutation in the fumarate hydratase gene, which codes for an enzyme (fumarase) that has previously been implicated in sperm number and motility. More recently, heterozygous mutations in this gene have been associated with HLRCC. However, male infertility is not a recognized manifestation of this condition. A comprehensive medical (including family) history and physical examination are important when evaluating male infertility. Genetics consultation enabled our patient and his family to begin appropriate cancer screening and provided reproductive options, including prenatal/preimplantation diagnosis. Further studies of the relationship between fumarase, HLRCC, and male infertility are needed to provide accurate counseling to families and to better understand genotype-phenotype correlations.

Multiple Cutaneous and Uterine Leiomyomas Associated with Gastric Gist

Background: There are a number of reports documenting familial cases of leiomyomatosis cutis associated with uterine leiomyomata. However, to our knowledge, the association of gastrointestinal stromal tumour (GIST) with this entity has not as yet been reported. We report an interesting case of cutaneous leiomyomatosis, metachronous uterine leiomyomata, and a gastric GIST in a 43-year-old woman. Observation: The patient had previously undergone two separate uterine myomectomies at ages 25 and 26 years, respectively, followed by a hysterectomy at 27 years. At 36 years she underwent partial gastrectomy for excision of GIST and this was followed by the development of extensive, symptomatic cutaneous leiomyomata at 43 years. In the report, we have documented histological, immunohistochemical and clinical observations and furthermore report on the therapeutic measures undertaken. Conclusion: We report an interesting association of cutaneous leiomyomatosis, uterine leiomyomas and GIST.

Multiple Cutaneous and Uterine Leiomyomas Associated with Gastric Gist

There are a number of reports documenting familial cases of leiomyomatosis cutis associated with uterine leiomyomata. However, to our knowledge, the association of gastrointestinal stromal tumour (GIST) with this entity has not as yet been reported. We report an interesting case of cutaneous leiomyomatosis, metachronous uterine leiomyomata, and a gastric GIST in a 43-year-old woman. The patient had previously undergone two separate uterine myomectomies at ages 25 and 26 years, respectively, followed by a hysterectomy at 27 years. At 36 years she underwent partial gastrectomy for excision of GIST and this was followed by the development of extensive, symptomatic cutaneous leiomyomata at 43 years. In the report, we have documented histological, immunohistochemical and clinical observations and furthermore report on the therapeutic measures undertaken. We report an interesting association of cutaneous leiomyomatosis, uterine leiomyomas and GIST.

Germline fumarate hydratase mutations and evidence for a founder mutation underlying multiple cutaneous and uterine leiomyomata

Multiple cutaneous and uterine leiomyomata syndrome (MCL) is an autosomal dominant disease characterized by the presence of concurrent benign tumors of smooth muscle origin (leiomyoma) in the skin and uterus of affected females, and in the skin of affected males. MCL can also be associated with type II papillary renal cell cancer (HLRCC). The genetic locus for MCL and HLRCC was recently mapped to chromosome 1q42.3-43 and subsequently, dominantly inherited mutations in the fumarate hydratase gene ( FH ) were identified. Importantly, analysis of the FH gene in tumors of MCL patients revealed a second mutation inactivating the wild-type allele in some tumors. Based on these findings, it has been suggested that FH may function as a tumor suppressor gene in MCL. Here, we report the analysis of the FH gene in a group of 11 MCL families, with the identification of 8 different mutations accounting for the disease in all families. One of the mutations, 905-1G>A, has been identified in 4 families of Iranian origin. The analysis of highly polymorphic markers in the vicinity of the FH gene showed a shared haplotype in these 4 families, suggesting that 905-1G>A represents a founder mutation. Collectively, identification of 5 novel and 3 recurrent mutations further supports the role of FH in the pathogenesis of MCL.

Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer.

Uterine leiomyomata (fibroids) are common and clinically important tumors, but little is known about their etiology and pathogenesis. We previously mapped a gene that predisposes to multiple fibroids, cutaneous leiomyomata and renal cell carcinoma to chromosome 1q42.3-q43 (refs 4-6). Here we show, through a combination of mapping critical recombinants, identifying individuals with germline mutations and screening known and predicted transcripts, that this gene encodes fumarate hydratase, an enzyme of the tricarboxylic acid cycle. Leiomyomatosis-associated mutations are predicted to result in absent or truncated protein, or substitutions or deletions of highly conserved amino acids. Activity of fumarate hydratase is reduced in lymphoblastoid cells from individuals with leiomyomatosis. This enzyme acts as a tumor suppressor in familial leiomyomata, and its measured activity is very low or absent in tumors from individuals with leiomyomatosis. Mutations in FH also occur in the recessive condition fumarate hydratase deficiency, and some parents of people with this condition are susceptible to leiomyomata. Thus, heterozygous and homozygous or compound heterozygous mutants have very different clinical phenotypes. Our results provide clues to the pathogenesis of fibroids and emphasize the importance of mutations of housekeeping and mitochondrial proteins in the pathogenesis of common types of tumor.

Localization of a Gene ( MCUL1) for Multiple Cutaneous Leiomyomata and Uterine Fibroids to Chromosome 1q42.3-q43

Dominant transmission of multiple uterine and cutaneous smooth-muscle tumors is seen in the disorder multiple leiomyomatosis (ML). We undertook a genomewide screen of 11 families segregating ML and found evidence for linkage to chromosome 1q42.3-q43 (maximum multipoint LOD score 5.40). Haplotype construction and analysis of recombinations permitted the minimal interval containing the locus, which we have designated "MCUL1," to be refined to an approximately 14-cM region flanked by markers D1S517 and D1S2842. Allelic-loss studies of tumors indicated that MCUL1 may act as a tumor suppressor. Identification of MCUL1 should have wide interest, since this gene may harbor low-penetrance variants predisposing to the common form of uterine fibroids and/or may undergo somatic mutation in sporadic leiomyomata.

Pharmacological modulation of cold-induced pain in cutaneous leiomyomata.

In two patients with painful cutaneous leiomyomata, induction of pain by the application of an ice cube allowed assessment of a number of topical and systemic treatments aimed at reducing or preventing the pain. In one patient the alpha-adrenoceptor blocker, phenoxybenzamine alleviated cold-induced pain. In the second patient, topical 9% hyoscine hydrobromide (an anticholinergic agent) decreased pain induced by the ice cube, but was not helpful in reducing lesional pain due to cold weather.

9p trisomy/18p distal monosomy and multiple cutaneous leiomyomata

In this report a severely mentally retarded adult female with 9p trisomy/18pter monosomy is described. In addition to a 9p trisomy phenotype this patient presented with multiple cutaneous leiomyomata. The question is raised whether the concurrence of the chromosomal anomaly and the multiple skin tumors in this patient indicates another example of a specific chromosomal deletion (18pter) in a dominantly inherited multiple human tumor.

Léiomyomes multiples traités par nifédipine

The authors describe a new case of multiple cutaneous leiomyomata: a female patient aged 33 presents lesions in hundreds causing severe pain. The subjective symptoms are highly improved by the calcium antagonist nifedipine.

Multiple cutaneous leiomyomata and erythrocytosis with demonstration of erythropoietic activity in the cutaneous leiomyomata

SUMMARY We report the case of a 41-year-old woman with multiple cutaneous and uterine leiomyomata. The erythropoietic activity demonstrated in a cutaneous leiomyoma might account in part for her secondary erythrocytosis. The painful attacks were completely suppressed by phenoxybenzamine, an alpha adrenergic blocking agent.

Erythrocytosis Associated with Multiple Cutaneous Leiomyomata: Report of a Case with Demonstration of Erythropoietic Activity in the Tumour

A patient with leiomyomata of the skin and erythrocytosis is reported. After surgical removal of the larger skin tumours there was remission of the haematologic abnormalities and the erythrocytosis and the red cell mass decreased to normal levels. The raised serum erythropoietin levels were reduced but remained slightly elevated and less than those recorded prior to surgery. Tumour extracts contained significant erythropoietic activity. This seems to be the first documented case of erythrocytosis associated with skin leiomyomata.

Cutaneous leiomyomata in two brothers.

SUMMARY A patient with multiple cutaneous leiomyomata of pilar origin is described. The hereditary aspects of the condition are stressed and the clinical features and histopathology are briefly reviewed.

Cutaneous leiomyomata with uterine leiomyomata

Abstract i not available.

Cutaneous leiomyomata with uterine leiomyomata.

Cutaneous leiomyomata with uterine leiomyomata.

Polycythemia (Erythrocytosis) Associated with Uterine Fibroids: A Case Report with Erythropoietic Activity Demonstrated in the Tumor.

s1 May 1968Polycythemia (Erythrocytosis) Associated with Uterine Fibroids: A Case Report with Erythropoietic Activity Demonstrated in the Tumor.Edward J. Hertko, M.D., F.A.C.P.Edward J. Hertko, M.D., F.A.C.P.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-68-5-1169_1 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptSince 1953 the association of polycythemia with uterine fibroids has been reported 13 times. Various theories have been advanced as to the possible cause of the polycythemia, but none have been proved. One of the theories advanced was that the tumor might produce erythropoietin (erythrocytosis stimulating factor—ESF). This factor has been shown to be the etiological agent in the development of polycythemia associated with other tumors, such as renal carcinoma, cerebellar hemangioblastoma, and renal cysts.I have had a recent patient with polycythemia associated with uterine fibroids. After surgical removal of the fibroids her blood count returned to normal levels... This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: Des Moines, Iowa PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited ByMore Than a Myoma: A Review of Myomatous Erythrocytosis SyndromeMesenchymal Tumors of the UterusErythrocytosis Associated with a Dermoid Cyst of the Ovary and Erythropoietic Activity of the Tumour FluidParaneoplastische endokrine SyndromePolycythaemia and Erythropoietin Producing Uterine FibromyomaErythrocytosis Associated with Multiple Cutaneous Leiomyomata: Report of a Case with Demonstration of Erythropoietic Activity in the TumourErythrocytosis due to erythropoietin-producing uterine fibromyomaECTOPIC HORMONE PRODUCTION BY NON-ENDOCRINE TUMOURSStudies on the Mechanism of Erythrocytosis Associated with a Uterine FibromyomaSecondary Polycythaemia due to a Uterine Fibromyoma Producing ErythropoietinPRIMARY BENIGN ERYTHROCYTOSIS AND ABNORMAL RENAL PERFUSIONUTERINE FIBROMYOMATA AND SECONDARY POLYCYTHAEMIA 1 May 1968Volume 68, Issue 5Page: 1169-1169KeywordsBlood countsErythropoietinPolycythemia Issue Published: 1 May 1968 PDF DownloadLoading ...